Year: 2021
Type: article
Abstract: Here we report the generation of a multimodal cell census and atlas of the mammalian primary motor cortex as the initial product of the BRAIN Initiative Cell Census Network (BICCN). This was achieved by coordinated large-scale analyses of single-cell transcriptomes, chromatin accessibility, DNA methylomes, spatially resolved single-cell transcriptomes, morphological and electrophysiological properties and cellular resolution input–output mapping, integrated through cross-modal computational analysis. Our results advance the collective knowledge and understanding of brain cell-type organization 1–5 . First, our study reveals a unified molecular genetic landscape of cortical cell types that integrates their transcriptome, open chromatin and DNA methylation maps. Second, cross-species analysis achieves a consensus taxonomy of transcriptomic types and their hierarchical organization that is conserved from mouse to marmoset and human. Third, in situ single-cell transcriptomics provides a spatially resolved cell-type atlas of the motor cortex. Fourth, cross-modal analysis provides compelling evidence for the transcriptomic, epigenomic and gene regulatory basis of neuronal phenotypes such as their physiological and anatomical properties, demonstrating the biological validity and genomic underpinning of neuron types. We further present an extensive genetic toolset for targeting glutamatergic neuron types towards linking their molecular and developmental identity to their circuit function. Together, our results establish a unifying and mechanistic framework of neuronal cell-type organization that integrates multi-layered molecular genetic and spatial information with multi-faceted phenotypic properties.
Source: Nature
Authors: BRAIN Initiative Cell Census Network (BICCN), BRAIN Initiative Cell Census Network (BICCN) Corresponding authors, Edward M. Callaway, Hong-Wei Dong, Joseph R. Ecker, Michael J. Hawrylycz, Z. Josh Huang, Ed S. Lein, John Ngai, Pavel Osten, Bing Ren, Andreas Savas Tolias, Owen White, Hongkui Zeng, Xiaowei Zhuang, BICCN contributing principal investigators, Giorgio A. Ascoli, M. Margarita Behrens, Jerold Chun, Guoping Feng, James C. Gee, Satrajit S. Ghosh, Yaroslav O. Halchenko, Ronna Hertzano, Byung Kook Lim, Maryann E. Martone, Lydia Ng, Lior Pachter, Alexander J. Ropelewski, Timothy L. Tickle, X. William Yang, Kun Zhang, Principal manuscript editors, Manuscript writing and figure generation, Trygve E. Bakken, Philipp Berens, Tanya L. Daigle, Julie A. Harris, Nikolas L. Jorstad, Brian E. Kalmbach, Dmitry Kobak, Yang Eric Li, Hanqing Liu, Katherine S. Matho, Eran A. Mukamel, Maitham Naeemi, Federico Scala, Pengcheng Tan, Jonathan T. Ting, Fangming Xie, Meng Zhang, Zhuzhu Zhang, Jingtian Zhou, Brian Zingg, Analysis coordination, Integrated data analysis, Ethan Armand, Zizhen Yao, scRNA-seq and snRNA-seq data generation and processing, Darren Bertagnolli, Tamara Casper, Kirsten Crichton, Nick Dee, Dinh Diep, Song-Lin Ding, Weixiu Dong, Elizabeth L. Dougherty, Olivia Fong, Melissa Goldman, Jeff Goldy, Rebecca D. Hodge, Lijuan Hu, C. Dirk Keene, Fenna M. Krienen, Matthew Kroll, Blue B. Lake, Kanan Lathia, Sten Linnarsson, Christine S. Liu, Evan Z. Macosko, Steven A. McCarroll, Delissa McMillen, Naeem M. Nadaf, Thuc Nghi Nguyen, Carter R. Palmer, Thanh Pham, Nongluk Plongthongkum, Nora M. Reed, Aviv Regev, Christine Rimorin, William J. Romanow, Steven Savoia, Kimberly Siletti, Kimberly Smith, Josef Sulc, Bosiljka Tasic, Michael Tieu, Amy Torkelson, Herman Tung, Cindy T. J. van Velthoven, Charles R. Vanderburg, Anna Marie Yanny, ATAC-seq data generation and processing, Rongxin Fang, Xiaomeng Hou, Jacinta D. Lucero, Julia K. Osteen, Antonio Pinto-Duarte, Olivier Poirion, Sebastian Preissl, Xinxin Wang, Methylcytosine data production and analysis, Andrew I. Aldridge, Anna Bartlett, Lara Boggeman, Carolyn O’Connor, Rosa G. Castanon, Huaming Chen, Conor Fitzpatrick, Chongyuan Luo, Joseph R. Nery, Michael Nunn, Angeline C. Rivkin, Wei Tian, Epi-retro-seq data generation and processing, Bertha Dominguez, Tony Ito-Cole, Matthew Jacobs, Xin Jin, Cheng-Ta Lee, Kuo-Fen Lee, Paula Assakura Miyazaki, Yan Pang, Mohammad Rashid, Jared B. Smith, Minh Vu, Elora Williams, ‘Omics data analysis, Tommaso Biancalani, A. Sina Booeshaghi, Megan Crow, Sandrine Dudoit, Stephan Fischer, Jesse Gillis, Qiwen Hu, Peter V. Kharchenko, Sheng-Yong Niu, Vasilis Ntranos, Elizabeth Purdom, Davide Risso, Hector Roux de Bézieux, Saroja Somasundaram, Kelly Street, Valentine Svensson, Eeshit Dhaval Vaishnav, Koen Van den Berge, Joshua D. Welch, Tracing and connectivity data generation, Xu An, Helen S. Bateup, Ian Bowman, Rebecca K. Chance, Nicholas N. Foster, William Galbavy, Hui Gong, Lin Gou, Joshua T. Hatfield, Houri Hintiryan, Karla E. Hirokawa, Gukhan Kim, Daniel J. Kramer, Anan Li, Xiangning Li, Qingming Luo, Rodrigo Muñoz-Castañeda, David A. Stafford, Morphology data generation and reconstruction, Zhao Feng, Xueyan Jia, Shengdian Jiang, Tao Jiang, Xiuli Kuang, Rachael Larsen, Phil Lesnar, Yaoyao Li, Yuanyuan Li, Lijuan Liu, Hanchuan Peng, Lei Qu, Miao Ren, Zongcai Ruan, Elise Shen, Yuanyuan Song, Wayne Wakeman, Peng Wang, Yimin Wang, Yun Wang, Lulu Yin, Jing Yuan, Sujun Zhao, Xuan Zhao, OLST/STPT and other data generation, Arun Narasimhan, Ramesh Palaniswamy, Morphology, connectivity and imaging analysis, Samik Banerjee, Liya Ding, Dhananjay Huilgol, Bingxing Huo, Hsien-Chi Kuo, Sophie Laturnus, Xu Li, Partha P. Mitra, Judith Mizrachi, Quanxin Wang, Peng Xie, Feng Xiong, Yang Yu, Spatially resolved single-cell transcriptomics (MERFISH), Stephen W. Eichhorn, Multimodal profiling (Patch-seq), Jim Berg, Matteo Bernabucci, Yves Bernaerts, Cathryn René Cadwell, Jesus Ramon Castro, Rachel Dalley, Leonard Hartmanis, Gregory D. Horwitz, Xiaolong Jiang, Andrew L. Ko, Elanine Miranda, Shalaka Mulherkar, Philip R. Nicovich, Scott F. Owen, Rickard Sandberg, Staci A. Sorensen, Zheng Huan Tan, Transgenic tools, Shona Allen, Dirk Hockemeyer, Angus Y. Lee, Matthew B. Veldman, NeMO archive and analytics, Ricky S. Adkins, Seth A. Ament, Héctor Corrada Bravo, Robert Carter, Apaala Chatterjee, Carlo Colantuoni, Jonathan Crabtree, Heather Creasy, Victor Felix, Michelle Giglio, Brian R. Herb, Jayaram Kancherla, Anup Mahurkar, Carrie McCracken, Lance Nickel, Dustin Olley, Joshua Orvis, Michael Schor, Greg Hood, DANDI archive, Benjamin Dichter, Michael Grauer, Brian Helba, Anita Bandrowski, Nikolaos Barkas, Benjamin Carlin, Florence D. D’Orazi, Kylee Degatano, Thomas H. Gillespie, Farzaneh Khajouei, Kishori Konwar, Carol Thompson, Project management, Kathleen Kelly, Stephanie Mok, Susan Sunkin
Institutions: Salk Institute for Biological Studies, University of California, Los Angeles, University of Southern California, Allen Institute for Brain Science, Howard Hughes Medical Institute, Cold Spring Harbor Laboratory, Duke University, Duke Medical Center, University of California, Berkeley, University of California San Diego, Baylor College of Medicine, University of Maryland, Baltimore, Ludwig Cancer Research, Harvard University, George Mason University, Sanford Burnham Prebys Medical Discovery Institute, McGovern Institute for Brain Research, Massachusetts Institute of Technology, University of Pennsylvania, Broad Institute, Dartmouth College, Stanley Center for Psychiatric Research, California Institute of Technology, Pittsburgh Supercomputing Center, Carnegie Mellon University, Klarman Cell Observatory, University of Tübingen, Bernstein Center for Computational Neuroscience Tübingen, University of Washington, Anhui University, Wenzhou Medical University, Tsinghua University, Karolinska Institutet, University of California, San Francisco, University of Padua, Dana-Farber Cancer Institute, University of Michigan, Wuhan National Laboratory for Optoelectronics, Huazhong University of Science and Technology, Ghent University, Chan Zuckerberg Biohub San Francisco, Stony Brook University, Southeast University, Hainan University, Shanghai University, Stanford Medicine, Stanford University, University of Maryland, College Park, Johns Hopkins University, Johns Hopkins Medicine, Harborview Medical Center, Innovative Genomics Institute, CatalystNeuro, Kitware (United States)
Language: English
Subfield: Molecular Biology
Domain: Life Sciences
Open Access status: hybrid
Estimated APC paid: $11,390
Funders: National Science Foundation, Howard Hughes Medical Institute, Hearing Health Foundation, Institute of Translational Health Sciences, Deutsche Forschungsgemeinschaft, National Natural Science Foundation of China, Bundesministerium für Bildung und Forschung, National Institutes of Health, Klarman Cell Observatory, Broad Institute, National Institute on Aging, National Institute of Mental Health, National Eye Institute, National Cancer Institute, National Institute on Deafness and Other Communication Disorders, National Institute of Neurological Disorders and Stroke, National Center for Advancing Translational Sciences, Office of Research Infrastructure Programs, National Institutes of Health
Awards: A Community Resource for Single Cell Data in the Brain, A multimodal atlas of human brain cell types, Toward a human adult brain cell atlas with single-cell technologies, Single cell transcriptional and epigenomic atlas of the macaque brain across the lifespan, G1736999115, G1752525184, Cell atlas of mouse brain-spinal cord connectome, Collaboratory for atlasing cell type anatomy in the female and male mouse brain, G2069825596, G2074461085, Towards integrated 3D reconstruction of whole human brains at subcellular resolution, Modeling Alzheimer's Disease Related Dementias in the Marmoset, A Comprehensive Center for Mouse Brain Cell Atlas, Dendritome mapping of genetically-defined and sparsely-labeled cortical and striatal projection neurons, G2296807306, Linking molecular and anatomical features of brain cell identity through computational data integration, Deciphering the building blocks of the macaque prefrontal cortical microcircuit, G2786010011, G2842013730, G2923856803, Generation and Description of Neuronal Morphology and Connectivity, G3292149396, G3338513347, G3635313588, Institute of Translational Health Sciences, G4066625888, The gEAR portal - Advancing Data Sharing, Analysis and Discovery for Hearing and Balance Research, Deciphering the transcriptomic signatures, physiology, and connectivity of the specialized morphotypes in macaque insular cortex, G4652911664, Center for Epigenomics of the Mouse Brain Atlas (CEMBA), G4697300529, Establishing a Comprehensive and Standardized Cell Type Characterization Platform, G4801963049, G506232429, A Molecular and Cellular Atlas of the Marmoset Brain, SFB 1233: Robustheit des Sehens Prinzipien der Inferenz und neuronale Mechanismen, Verbundprojekt TUEAI: Tübingen AI Center, The Mouse Connectome Project Phase III: Assembling the global neural networks of the mouse brain, Development of tools for cell-type specific labeling of human and mouse neocortical neurons, Anatomical characterization of neuronal cell types of the mouse brain, Epigenomic cell-type classification and regulatory element identification in the human brain, G569996611, Cytoskeletal mechanisms of dendrite arbor shape development, BD FACSAria Fusion for Flow Cytometry Core Facility, G6612273523, Illuminating Neurodevelopment through Integrated Analysis and Vizualization of Multi-Omic Data, A Cellular Resolution Census of the Developing Human Brain, Modeling Alzheimer's Disease Related Dementias in the Marmoset, Zelltyp-spezifische neuronale Berechnungen, A comprehensive whole-brain atlas of cell types in the mouse, EXC 2064: Maschinelles Lernen: Neue Perspektiven für die Wissenschaft, High-throughput robotic analysis of integrated neuronal phenotypes, 基于深度聚类的三维线虫细胞协同分割与识别研究, Genetic models of sporadic Alzheimers Disease in the marmoset, Development of aberrant cortical interneuron circuitry in genetic mouse models of absence epilepsy, Imaging and Analysis Techniques to Construct a Cell Census Atlas of the Human Brain, G9000211979, G9000258375, Washington National Primate Research Center, A Confocal Fluorescence Microscopy Brain Data Archive, Cancer Center Support Grant (CCSG), DANDI: Distributed Archives for Neurophysiology Data Integration, A BRAIN Initiative Resource: The Neuroscience Multi-omic Data Archive, University of Washington Alzheimer's Disease Research Center
OpenAlex ID: W4242111955